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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
  • C07C45/75—Reactions with formaldehyde
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
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  • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D277/10—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
• • C—CHEMISTRY; METALLURGY
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  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D277/70—Sulfur atoms
  • C07D277/72—2-Mercaptobenzothiazole
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

• the invention relates to a method for producing an ⁇ -hydroxy ketone compound, and the like.
• Patent Document 1 discloses a method of using a catalyst prepared from 3-ethylbenzothiazolium salt and a basic compound and a method of using a catalyst prepared from 3-benzylthiazolium salt and a basic compound.
• the aim to be solved by the present invention is to provide an innovative method for producing an ⁇ -hydroxy ketone compound, and the like.
• the invention is as follows.
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 0 denotes a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• W 0 denotes an aryl which may have a substituent or a halogen atom;
• X ⁇ denotes an anion;
• n denotes 1 or 2; in the case n is 2, 2 groups denoted by W 0 may be mutually the same or different; and all or some of a plurality of groups denoted by R 0 may be the same or different).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• W 1 and W 2 independently denote an aryl which may have a substituent or a halogen atom; and
• X ⁇ denotes an anion).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• R 8 denotes a hydrogen atom or an alkyl which may have a substituent;
• W 1 denotes an aryl which may have a substituent or a halogen atom; and
• X ⁇ denotes an anion).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 0 denotes a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• W 0 denotes an aryl which may have a substituent or a halogen atom;
• n denotes 1 or 2; in the case n is 2, 2 groups denoted by W 0 may be mutually the same or different; and all or some of a plurality of groups denoted by R 0 may be the same or different).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent; and
• W 1 and W 2 independently denote an aryl which may have a substituent or a halogen atom).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• R 8 denotes a hydrogen atom or an alkyl which may have a substituent; and
• W 1 denotes an aryl which may have a substituent or a halogen atom).
• R 6 denotes a hydrogen atom, an alkyl which may have a substituent, an aryl which may have a substituent, or a heteroaryl which may have a substituent
• R 6 denotes a hydrogen atom, an alkyl which may have a substituent, an aryl which may have a substituent, or a heteroaryl which may have a substituent
• R 7 is different from R 6 and denotes a hydrogen atom, an alkyl which may have a substituent, an aryl which may have a substituent, or a heteroaryl which may have a substituent).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 0 denotes a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• W 0 denotes an aryl which may have a substituent or a halogen atom;
• X ⁇ denotes an anion;
• n denotes 1 or 2; in the case n is 2, 2 groups denoted by W 0 may be mutually the same or different; and all or some of a plurality of groups denoted by R 0 may be the same).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 2 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• W 1 and W 2 independently denote an aryl which may have a substituent or a halogen atom; and
• X ⁇ denotes an anion
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• R 8 denotes a hydrogen atom or an alkyl which may have a substituent;
• W 4 denotes an aryl which may have a substituent or a halogen atom; and
• X ⁇ denotes an anion
• R 1 and R 2 independently denote a C 1-10 alkyl, or R 1 and R 2 are bonded to each other to form a C 5-10 cycloalkene ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom or a C 1-10 alkyl;
• R 8 denotes a C 1-10 alkyl;
• W 1 denotes a C 6-10 aryl which may have a substituent.
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 0 denotes a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• W 0 denotes an aryl which may have a substituent or a halogen atom;
• n denotes 1 or 2; in the case n is 2, 2 groups denoted by W 0 may be mutually the same or different; and all or some of a plurality of groups denoted by R 0 may be the same).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent; and
• W 1 and W 2 independently denote an aryl which may have a substituent or a halogen atom).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• R 8 denotes a hydrogen atom or an alkyl which may have a substituent; and
• W 4 denotes an aryl which may have a substituent or a halogen atom).
• R 1 and R 2 independently denote a C 1-10 alkyl, or R 1 and R 2 are bonded to each other to form a C 5-10 cycloalkene ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom or a C 1-10 alkyl;
• R 8 denotes a C 1-10 alkyl;
• W 1 denotes a C 6-10 aryl which may have a substituent.
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 0 denotes a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent; all or some of 4 groups denoted by R 0 may be the same;
• W 0 ′ denotes an aryl which may have a substituent;
• X ⁇ denotes an anion; and n denotes the same as above
• step B of oxidizing the 3-(aryl-substituted aryl)-2-thiazole-thione compound defined by the formula (7) obtained in the step A.
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent; and
• W 1 and W 2 independently denote an aryl which may have a substituent or a halogen atom).
• R 1 and R 2 independently denote a hydrogen atom, an alkyl which may have a substituent, an alkoxycarbonyl which may have a substituent, an alkylcarbonyl which may have a substituent, or an aryl which may have a substituent, or R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 ;
• R 3 , R 4 , and R 5 independently denote a hydrogen atom, a halogen atom, an alkyl which may have a substituent, or an aryl which may have a substituent;
• R 8 denotes a hydrogen atom or an alkyl which may have a substituent; and
• W 1 denotes an aryl which may have a substituent or a halogen atom).
• the present invention provides an innovative method for producing an ⁇ -hydroxy ketone compound, and the like.
• the present invention is advantageous in terms of improvement of selectivity in production of an ⁇ -hydroxy ketone compound per unit catalyst amount.
• the present invention is characterized by carrying out a coupling reaction (hereinafter, sometimes referred to as the present reaction) of an aldehyde compound in the presence of a base compound and a thiazolium salt defined by a formula (1)
• thiazolium salt (1) (hereinafter, sometimes referred to as thiazolium salt (1)).
• the thiazolium salt (1) is preferably a thiazolium salt defined by a formula (1′)
• thiazolium salt (1′) or a thiazolium salt defined by a formula (1′′)
• thiazolium salt (1′′) (hereinafter, sometimes referred to as thiazolium salt (1′′)).
• Examples of an alkyl denoted by R 1 and R 2 may be C 1-10 straight chain, branched chain, and cyclic alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, decyl, cyclopropyl, 2,2-dimethylcyclopropyl, cyclopentyl, cyclohexyl, and menthyl.
• cyclic alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, decyl, cyclopropyl, 2,2-dimethylcyclopropyl, cyclopentyl, cyclohexyl, and menthyl.
• Examples of a substituent which the alkyl denoted by R 1 and R 2 may have may be a C 6-10 aryl, which may have a C 1-10 alkoxy, such as phenyl, naphthyl, 4-methylphenyl, and 4-methoxyphenyl; a C 1-10 alkoxy, which may have a fluorine atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butyloxy, tert-butoxy, and trifluoromethoxy; a C 6-10 aryl-containing C 1-10 alkoxy, which may have a C 1-10 alkoxy, such as benzyloxy, 4-methylbenzyloxy, and 4-methoxybenzyloxy; a C 1-10 alkoxy having a C 6-10 aryloxy-containing C 6-10 aryl such as 3-phenoxybenzyloxy; a C 6-10 aryloxy, which may have a C 1-10 alkoxy,
• Examples of an alkyl having a substituent and denoted by R 1 and R 2 may be fluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, methoxyethyl, benzyl, 4-fluorobenzyl, 4-methylbenzyl, phenoxymethyl, 2-oxopropyl, 2-oxobutyl, phenacyl, and 2-carboxyethyl.
• Examples of an aryl denoted by R 1 and R 2 may be a C 6-10 aryl such as phenyl, 2-methylphenyl, 4-methylphenyl, and naphthyl.
• Examples of a substituent which the aryl may have may be a C 1-10 alkyl containing a C 1-10 alkoxy or a fluorine atom such as fluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, and methoxyethyl; a C 1-10 alkoxy, which may have a C 1-10 alkoxy or a fluorine atom such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, cyclopentyloxy, fluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, and methoxyethoxy; and a halogen atom such as a fluorine atom and a chlorine atom.
• Examples of an aryl having a substituent may be 4-chlorophenyl and 4-methoxyphenyl.
• Examples of an alkoxycarbonyl denoted by R 1 and R 2 may be C 2-11 straight chain, branched chain, and cyclic alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, decyloxycarbonyl, cyclopropoxycarbonyl, and cyclohexyloxycarbonyl.
• alkoxycarbonyl denoted by R 1 and R 2 may be C 2-11 straight chain, branched chain, and cyclic alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, decyloxycarbonyl, cyclopropoxycarbonyl,
• Examples of a substituent which the alkoxycarbonyl denoted by R 1 and R 2 may have may be a C 6-10 aryl, which may have a C 1-10 alkoxy, such as phenyl, naphthyl, 4-methylphenyl, and 4-methoxyphenyl; a C 1-10 alkoxy, which may have a fluorine atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and trifluoromethoxy; a C 6-10 aryl-containing C 1-10 alkoxy, which may have a C 1-10 alkoxy, such as benzyloxy, 4-methylbenzyloxy, and 4-methoxybenzyloxy; a C 1-10 alkoxy having a C 6-10 aryloxy-containing C 6-10 aryl such as 3-phenoxybenzyloxy; a C 6-10 aryloxy, which may have a C 1-10 alkoxy
• Examples of an alkoxycarbonyl having a substituent and defined by R 1 and R 2 may be fluoromethoxycarbonyl, trifluoromethoxycarbonyl, methoxymethoxycarbonyl, ethoxymethoxycarbonyl, benzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-methylbenzyloxycarbonyl, phenoxymethoxycarbonyl, 2-oxopropoxycarbonyl, and 2-oxobutoxycarbonyl.
• Examples of an alkylcarbonyl denoted by R 1 and R 2 may be C 2-11 straight chain, branched chain, and cyclic alkylcarbonyl such as acetyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, decylcarbonyl, cyclopropylcarbonyl, and cyclohexylcarbonyl.
• cyclic alkylcarbonyl such as acetyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, decylcarbonyl, cyclopropylcarbonyl, and cyclohexylcarbonyl.
• Examples of a substituent which an alkylcarbonyl denoted by R 1 and R 2 may have may be a C 6-10 aryl, which may have a C 1-10 alkoxy, such as phenyl, naphthyl, 4-methylphenyl, and 4-methoxyphenyl; a C 1-10 alkoxy, which may have a fluorine atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, sec-butyloxy, tert-butyloxy, and trifluoromethyloxy; a C 6-10 aryl-containing C 1-10 alkoxy, which may have a C 1-10 alkoxy, such as benzyloxy, 4-methylbenzyloxy, and 4-methoxybenzyloxy; a C 1-10 alkoxy having a C 6-10 aryloxy-containing C 6-10 aryl such as 3-phenoxybenzyl
• Examples of an alkylcarbonyl having a substituent and defined by R 1 and R 2 may be fluoromethylcarbonyl, trifluoromethylcarbonyl, methoxymethylcarbonyl, ethoxymethylcarbonyl, benzylcarbonyl, 4-fluorobenzylcarbonyl, 4-methylbenzylcarbonyl, phenoxymethylcarbonyl, 2-oxopropylcarbonyl, and 2-oxobutylcarbonyl.
• R 1 and R 2 may be bonded to each other to form a ring together with the carbon atoms bonded to R 1 and R 2 and examples of the ring may be cycloalkene rings such as a cyclopentene, a cyclohexene, and a cycloheptene. These rings may be substituted with a substituent which the alkyl may have in the case R 1 and R 2 do not form a ring.
• Examples of an alkyl denoted by R 0 , R 3 , R 4 , R 5 , and R 8 may be C 1-10 straight chain, branched chain, and cyclic alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, decyl, cyclopropyl, 2,2-dimethylcyclopropyl, cyclopentyl, cyclohexyl, and menthyl.
• cyclic alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, decyl, cyclopropyl, 2,2-dimethylcyclopropyl, cyclopentyl, cyclohexyl, and menthyl.
• Examples of a substituent which the alkyl denoted by R 0 , R 3 , R 4 , R 5 , and R 8 may have may be a C 6-10 aryl, which may have a C 1-10 alkoxy, such as phenyl, naphthyl, 4-methylphenyl, and 4-methoxyphenyl; a C 1-10 alkoxy, which may have a fluorine atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and trifluoromethoxy; a C 6-10 aryl-containing C 1-10 alkoxy, which may have a C 1-10 alkoxy, such as benzyloxy, 4-methylbenzyloxy, and 4-methoxybenzyloxy; a C 1-10 alkoxy having a C 6-10 aryloxy-containing C 6-10 aryl such as 3-phenoxybenzyloxy; a C 6-10 aryloxy
• Examples of an alkyl having a substituent and denoted by R 0 , R 3 , R 4 , R 5 , and R 8 may be fluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, methoxyethyl, benzyl, 4-fluorobenzyl, 4-methylbenzyl, phenoxymethyl, 2-oxopropyl, 2-oxobutyl, phenacyl, and 2-carboxyethyl.
• Examples of an aryl denoted by R 0 , R 3 , R 4 , and R 5 may be a C 6-10 aryl such as phenyl, 2-methylphenyl, 4-methylphenyl, and naphthyl.
• Examples of a substituent which the aryl may have may be a C 1-10 alkyl containing a C 1-10 alkoxy or a fluorine atom such as fluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, and methoxyethyl; a C 1-10 alkoxy which may have a C 1-10 alkoxy or a fluorine atom such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, cyclopentyloxy, fluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, and methoxyethoxy; and a halogen atom such as a fluorine atom and a chlorine atom.
• Examples of an aryl having a substituent may be 4-chlorophenyl and 4-methoxyphenyl.
• Examples of a halogen atom denoted by R 0 , R 3 , R 4 , and R 5 may be a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• W 1 and W 2 independently denote an aryl which may have a substituent or a halogen atom.
• Examples of an aryl denoted by W 0 , W 1 , and W 2 may be a C 6-20 aryl such as phenyl, naphthyl, anthryl, and phenanthryl.
• Examples of a substituent which the aryl may have are not particularly limited if they do not inhibit the present reaction and may include an alkyl which may have a substituent, an aryl which may have a substituent, an alkoxy which may have a substituent, a nitro group; a cyano group; a C 2-10 alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl; an acyl such as formyl, acetyl, and propionyl; a sulfo group; and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• Examples of an aryl which may have a substituent denoted by W 0 , W 1 , and W 2 may be a C 6-20 aryl such as 2-fluorophenyl, 2-nitronaphthyl, 2-cyanophenyl, 4-nitrophenyl, 2,6-dichlorophenyl, 2,4,6-tribromophenyl, 3,5-bis(trifluoromethyl)phenyl, 2-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, and 3,5-diphenylphenyl.
• Examples of a halogen atom denoted by W 0 , W 1 , and W 2 may be a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• R 1 and R 2 are independently a C 1-10 (more preferably a C 1-4 ) alkyl, or that R 1 and R 2 are bonded to each other to form a C 5-7 cycloalkene ring (more preferably a cyclohexene ring) together with the carbon atoms bonded to R 1 and R 2 ; it is more preferable that the carbon atom of the cycloalkene ring in the thiazolium ring S side (the 7th position in the cyclohexene ring) has a C 1-4 alkyl as a substituent; it is preferable that R 0 is a hydrogen atom, a halogen atom, or a C 1-10 alkyl; and it is preferable that W 0 is a C 6-10 aryl which may have a substituent.
• the aryl is more preferably phenyl having a substituent, even more preferably phenyl having a bulky group at one of the 3rd and the 5th positions, and still more preferably phenyl having a bulky group at the 3rd and the 5th positions.
• the bulky group may be phenyl, trifluoromethyl, tert-butyl, a chlorine atom, a bromine atom, an iodine atom, nitro, cyano, methoxycarbonyl, acyl, sulfo, and 3,4,5-trifluorophenyl.
• R 1 and R 2 are independently a C 1-10 (more preferably a C 1-4 ) alkyl, or that R 1 and R 2 are bonded to each other to form a C 5-7 cycloalkene ring (more preferably a cyclohexene ring) together with the carbon atoms bonded to R 1 and R 2 ; it is more preferable that the carbon atom of the cycloalkene ring in the thiazolium ring S side (the 7th position in the cyclohexene ring) has a C 1-4 alkyl as a substituent; it is preferable that R 3 , R 4 , and R 5 are independently a hydrogen atom, a halogen atom, or a C 1-10 alkyl; and it is preferable that W 1 and W 2 are independently a C 6-10 aryl which may have a substituent.
• the aryl is more preferably phenyl having a substituent, even more preferably phenyl having a bulky group at one of the 3rd and the 5th positions, and still more preferably phenyl having a bulky group at the 3rd and the 5th positions.
• the bulky group may be phenyl, trifluoromethyl, tert-butyl, a chlorine atom, a bromine atom, an iodine atom, nitro, cyano, methoxycarbonyl, acyl, sulfo, and 3,4,5-trifluorophenyl.
• R 1 and R 2 are independently a C o (more preferably a C 1-4 ) alkyl, or that R 1 and R 2 are bonded to each other to form a C 5-7 cycloalkene ring (more preferably a cyclohexene ring) together with the carbon atoms bonded to R 1 and R 2 ; it is more preferable that the carbon atom of the cycloalkene ring in the thiazolium ring S side (the 7th position in the cyclohexene ring) has a C 1-4 alkyl as a substituent; it is preferable that R 3 , R 4 , and R 5 are independently a hydrogen atom or a C 1-10 alkyl; it is preferable that R 8 is a C 1-10 alkyl; and it is preferable that W 1 is a C 6-10 aryl which may have a substituent.
• the aryl is more preferably phenyl having a substituent, even more preferably phenyl having a bulky group at one of the 3rd and the 5th positions, and still more preferably phenyl having a bulky group at the 3rd and the 5th positions.
• the bulky group may be phenyl, trifluoromethyl, tert-butyl, a chlorine atom, a bromine atom, an iodine atom, nitro, cyano, methoxycarbonyl, acyl, sulfo, and 3,4,5-trifluorophenyl.
• anion denoted by X may be a halide ion such as chloride ion, bromide ion, and iodide ion; an alkanesulfonate ion which may have a fluorine atom such as methanesulfonate and trifluoromethanesulfonate; acetate ion which may have a halogen atom such as trifluoroacetate and trichloroacetate ion; nitrate ion; perchlorate ion; a tetrahaloborate ion such as tetrafluoroborate and tetrachloroborate; a hexahalophosphate ion such as hexafluorophosphate; a hexahaloantimonate ion such as hexafluoroantimonate and hexachloroantimonate; a penta halide ion such as chloride ion
• Examples of a thiazolium salt (1′) may be 3-[2,6-di(phenyl)phenyl]-thiazolium chloride, 3-[2,6-di(phenyl)phenyl]-4,5-dimethylthiazolium chloride, 3-[2,6-di(phenyl)phenyl]-4,5-diethylthiazolium chloride, 3-[2,6-di(phenyl)phenyl]-4-methyl-5-acylthiazolium chloride, 3-[2,6-di(phenyl)phenyl]-4-methyl-5-methoxycarbonylthiazolium chloride, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-thiazolium chloride, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5-dimethylthiazolium chloride, 3-[2,6-bis(3-tert-butylpheny
• Examples may also include thiazolium salts (1′) obtained by substituting “chloride” in these thiazolium salts (1) with “iodide”, “bromide”, “methanesulfonate”, “trifluoromethanesulfonate”, “nitrate”, “perchlorate”, “tetrafluoroborate”, “tetrachloroborate”, “hexafluorophosphate”, “hexafluoroantimonate”, “hexachloroantimonate”, “pentafluorostannate”, “pentachlorostannate”, “tetraphenyl borate”, “tetrakis(pentafluorophenyl) borate”, and “tetrakis[3,5-bis(trifluoromethyl)phenyl] borate”.
• Such a thiazolium salt (1′) is a novel compound and may be produced by a method disclosed in, for example, Scheme 1 in J. Amer. Chem. Soc., vol. 130, p. 2234 (2008). That is, a thiazolium salt (1′) can be produced by a method involving steps of N-formylation by causing a reaction of 2,6-diaryl-substituted aryl-1-amine, or 2,6-dihalo-substituted aryl-1-amine, or 2-halo-6-aryl-substituted aryl-1-amine with formic acid/acetic anhydride; thiocarbonylation by causing a reaction of the obtained N-formylated product with a Lawesson's reagent, phosphorus pentasulfide, or the like; and a reaction of the obtained thiocarbonylated product and a 2-halo-substituted-1-one compound.
• Examples of a thiazolium salt (1′′) may be 3-[2-(phenyl)-6-methylphenyl]-thiazolium chloride, 3-[2-(phenyl)-6-methylphenyl]-4,5-dimethylthiazolium chloride, 3-[2-(phenyl)-6-ethylphenyl]-4,5-diethylthiazolium chloride, 3-[2-(phenyl)-6-methylphenyl]-4-methyl-5-acylthiazolium chloride, 3-[2-(phenyl)-6-ethylphenyl]-4-methyl-5-methoxycarbonylthiazolium chloride, 3-[2-(3,5-di-tert-butylphenyl)-6-methylphenyl]-thiazolium chloride, 3-[2-(3,5-di-tert-butylphenyl)-6-methylphenyl]-4,5-dimethylthiazolium chloride, 3-[2-(3,5-di-tert-butyl
• Examples may also include thiazolium salts (1′′) obtained by substituting “chloride” in these thiazolium salts (1′′) with “iodide”, “bromide”, “methanesulfonate”, “trifluoromethanesulfonate”, “nitrate”, “perchlorate”, “tetrafluoroborate”, “tetrachloroborate”, “hexafluorophosphate”, “hexafluoroantimonate”, “hexachloroantimonate”, “pentafluorostannate”, “pentachlorostannate”, “tetraphenyl borate”, “tetrakis(pentafluorophenyl) borate”, and “tetrakis[3,5-bis(trifluoromethyl)phenyl] borate”.
• Such a thiazolium salt (1′′) is a novel compound and may be produced by a method disclosed in, for example, Scheme 1 in J. Amer. Chem. Soc., vol. 130, p. 2234 (2008). That is, a thiazolium salt (1′′) can be produced by a method involving steps of N-formylation by causing a reaction of 2-aryl-substituted aryl-1-amine or 2-halo-substituted aryl-1-amine with formic acid/acetic anhydride; thiocarbonylation by causing a reaction of the obtained N-formylated product with a Lawesson's reagent, phosphorus pentasulfide, or the like; and a reaction of the obtained thiocarbonylated product and a 2-halo-substituted-1-one compound.
• Examples of a thiazolium salt (1) may be preferably 3-[2,6-di(phenyl)phenyl]-4,5-dimethylthiazolium salt, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5-dimethylthiazolium salt, 3-[(2,6-diphenyl-3,5-diisopropyl)phenyl]-4,5-dimethylthiazolium salt, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydrobenzothiazolium salt, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydro-7-ethylbenzothiazolium chloride, 3-[2,6-bis(3,5-di-tert-butylphenyl)-4-chlorophenyl]-4,5,
• a method for producing a compound as a thiazolium salt (1) in which W 0 is an aryl, that is, a thiazolium salt defined by the above-mentioned formula (8) may be preferably a method involving a step A of causing a coupling reaction of a 3-(halo-substituted aryl)-2-thiazole-thione compound defined by the above-mentioned formula (6) (hereinafter, referred to also a 3-(halo-substituted aryl)-2-thiazole-thione compound (6)) and an aryl compound defined by the above-mentioned formula (5) (hereinafter, referred to also as an aryl compound (5)) in the presence of a palladium catalyst and a step B of oxidizing the 3-(aryl-substituted aryl)-2-thiazole-thione compound (hereinafter, referred to
• a method for producing a 3-(halo-substituted aryl)-2-thiazole-thione compound (6) there is a method involving steps of causing a reaction of a halo-substituted aryl-1-amine and carbon disulfide in the presence of a dimethyl sulfoxide solvent and sodium hydroxide and causing a reaction of the obtained product and a 2-halo-substituted-1-one compound.
• Examples of a 3-(halo-substituted aryl)-2-thiazole-thione compound (6) may be 4,5-dimethyl-3-(2,6-difluorophenyl)-2(3H)-thiazole-thione, 4,5-dimethyl-3-(2,6-dichlorophenyl)-2(3H)-thiazole-thione, 4,5-dimethyl-3-(2,6-dibromophenyl)-2(3H)-thiazole-thione, 4,5-dimethyl-3-(2,6-diiodophenyl)-2(3H)-thiazole-thione, 4,5-diethyl-3-(2,6-dibromophenyl)-2(3H)-thiazole-thione, 3-(2,6-dibromophenyl)-2(3H)-thiazole-thione, 4,5-dimethyl-3-(2,4,6-tribromophenyl)-2(3H
• An aryl compound which can give a 3-(aryl-substituted aryl)-2-thiazole-thione compound (7) by causing a coupling reaction of the carbon atom to which a leaving group denoted by L in the formula (5) is bonded and the carbon atom having a halogen atom as a substituent in the 3-(halo-substituted aryl)-2-thiazole-thione compound (6) may be used as the aryl compound (5) without any particular limit.
• the leaving group denoted by L in the aryl compound (5) are —B(OH) 2 and —MgX 0 (wherein, X 0 denotes a halogen atom).
• the coupling reaction in the step A is preferably carried out in the presence of a base compound.
• a coupling reaction is so-called Suzuki-Miyaura coupling reaction and various improved methods have been developed and these methods may be used without any particular limit.
• the coupling reaction in the step A is preferably carried out in the presence of a zinc compound.
• a coupling reaction is so-called Negishi coupling reaction and various improved methods have been developed and these methods may be used without any particular limit.
• Examples of the palladium catalyst to be used in the step A may be palladium atom-containing compounds without any particular limit in the valence of palladium atom or their ligands and preferably palladium catalysts such as tetrakis(triphenylphosphine) palladium complex consisting of palladium atom and a ligand containing phosphorus atom.
• the palladium catalyst may be commercialized products or those prepared by causing a reaction of a phosphorus compound and a palladium compound.
• Examples of a palladium compound to be used for preparing the palladium catalyst may be 1,5-diphenyl-1,4-pentadien-3-one (palladium) complex, bis(1,5-diphenyl-1,4-pentadien-3-one) (palladium) complex, tris(1,5-diphenyl-1,4-pentadien-3-one)di(palladium)chloroform complex, allylpalladium chloride dimer, cyclooctadienepalladium dichloride, cyclooctadienepalladium dibromide, norbornadienepalladium dibromide, acetic acid palladium, palladiumacetylacetone, bis(acetonitrile)dichloro palladium, and bis(benzonitrile)dichloro palladium.
• These palladium compounds may be used alone or two or more kinds may be used in the form of a mixture.
• the phosphorus compound is a compound having one or more trivalent phosphorus atoms in a molecule and examples may be phosphorus compounds defined by
• R 9 , R 10 and R 11 independently denote an alkyl which may have a substituent, an aryl which may have a substituent, an alkoxy which may have a substituent, or an aryloxy which may have a substituent).
• Examples of an alkyl denoted independently by R 0 , R 10 and R 11 may be C 1-20 straight chain, branched chain, and cyclic alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-decyl, cyclopropyl, cyclopentyl, cyclohexyl, and menthyl.
• cyclic alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-decyl, cyclopropyl, cyclopentyl, cyclohexyl, and menthyl.
• alkyl groups may have at least one kind of group selected from the group consisting of alkoxy such as methoxy and ethoxy; a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom; alkoxycarbonyl such as methoxycarboxyl and ethoxycarbonyl; aryl such as phenyl, 1-naphthyl, and 2-naphthyl; and carboxy and examples of alkyl having such a group may be chloromethyl, fluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, methoxycarbonylmethyl, and benzyl.
• alkoxy such as methoxy and ethoxy
• a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom
• alkoxycarbonyl such as methoxycarboxyl and ethoxycarbonyl
• Examples of an aryl denoted independently by R 9 , R 10 and R 11 may be C 6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, and ferrocenyl.
• the aryl groups may have the above-mentioned alkyl, aryl, alkoxy, halogen atom and examples of an aryl which may have these groups may be phenyl, 1-naphthyl, 2-naphthyl, 2-methylphenyl, 4-chlorophenyl, 4-methylphenyl, and 4-methoxyphenyl.
• Examples of an alkoxy denoted independently by R 9 , R 10 and R 11 may be C 1-20 straight chain, branched chain, and cyclic alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-decyloxy, cyclopropoxy, cyclopentyloxy, and cyclohexyloxy.
• alkoxy groups may have at least one kind of group selected from the group consisting of alkoxy such as methoxy and ethoxy; a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom; alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl; aryl such as phenyl and naphthyl; and carboxy and examples of alkoxy having such a group may be chloromethoxy, fluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, 2-methoxyethoxy, and benzyloxy.
• alkoxy such as methoxy and ethoxy
• a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom
• alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl
• aryl such as phenyl and naphthy
• Examples of an aryloxy denoted independently by R 9 , R 10 and R 11 may be C 6-10 aryloxy such as phenoxy and naphthyloxy. These aryloxy groups may have a substituent such as the above-mentioned alkyl, aryl, alkoxy, and halogen atom. Examples of these aryloxy groups may be phenoxy, 1-naphthyloxy, 2-naphthyloxy, 2-methylphenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 4-methoxyphenoxy.
• R 9 , R 10 and R 11 may have a group defined by —PR 9 R 10 (wherein R 9 and R 10 independently denote as described above).
• Examples of such a phosphorus compound may be triphenylphosphine, tris(4-chlorophenyl)phosphine, tris(4-methoxyphenyl)phosphine, (2-di-tert-butylphosphino)biphenyl, bis(diphenylphosphino)ethane, bis(diphenylphosphino)propane, bis(diphenylphosphino)butane, 1,1′-bis(diphenylphosphino)ferrocene, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, 2,2′-bis(diphenylphosphino)-1,1′-biphenyl, 1,1′-oxybis[2,1-phenylenebis(diphenylphosphine)], triisopropylphosphine, tri(tert-butyl)phosphine, tricyclohexylphosphine
• the reaction of a phosphorus compound and a palladium compound may be carried out by mixing the phosphorus compound and the palladium compound in the presence of a solvent before the reaction in the step A or may be carried out in the reaction system in the presence of a 3-(halo-substituted aryl)-2-thiazole-thione compound (6), which is a raw material of the reaction in the step A, a base compound and also an arylboronic acid.
• the use amount of the palladium compound is preferably in a range of 0.000001 mol to 0.2 mol and more preferably in a range of 0.0001 mol to 0.1 mol to 1 mol of the 3-(halo-substituted aryl)-2-thiazole-thione compound (6).
• the use amount of the phosphorus compound is preferably in a range of 1 mol to 10 mol and more preferably in a range of 1 mol to 3 mol on the basis of phosphorus atom to 1 mol of palladium atom contained in the palladium compound.
• Examples of an aryl compound (5) having a leaving group —B(OH) 2 denoted by L; that is, an arylboronic acid; may be phenylboronic acid, 3,5-difluorophenylboronic acid, 1-naphthylboronic acid, 3,5-dinitrophenylboronic acid, 3,5-bis(trifluoromethyl)phenylboronic acid, 3,5-dimethylphenylboronic acid, 3,5-dimethoxyphenylboronic acid, 3,5-di-tert-butylphenylboronic acid, 3,5-diphenylphenylboronic acid, etc.
• the use amount of the arylboronic acid is for example in a range of 1 mol to 10 mol and preferably in a range of 1 mol to 5 mol to 1 mol of the 3-(halo-substituted aryl)-2-thiazole-thione compound (6).
• a base compound to be used together with the arylboronic acid in the step A may be those which do not inhibit the reaction and can neutralize boronic acid without any particular limit and examples may be alkali metal fluorides such as potassium fluoride, cesium fluoride, and rubidium fluoride; and alkali metal carbonates and alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate.
• alkali metal fluorides such as potassium fluoride, cesium fluoride, and rubidium fluoride
• alkali metal carbonates and alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate.
• the use amount of the base compound is preferably in a range of 1 mol to 5 mol and more preferably in a range of 1 mol to 3 mol to 1 mol of the arylboronic acid.
• Examples of an aryl compound (5) having a leaving group —MgX 0 denoted by L; that is, an aryl Grignard compound; may be phenylmagnesium bromide, 3,5-difluorophenylmagnesium bromide, 1-naphthylmagnesium bromide, 3,5-bis(trifluoromethyl)phenylmagnesium bromide, 3,5-dimethylphenylmagnesium bromide, 3,5-dimethoxyphenylmagnesium bromide, 3,5-di-tert-butylphenylmagnesium bromide, 3,5-diphenylphenylmagnesium bromide, phenylmagnesium chloride, 3,5-difluorophenylmagnesium chloride, 1-naphthylmagnesium chloride, 3,5-bis(trifluoromethyl)phenylmagnesium chloride, 3,5-dimethylphenylmagnesium chloride, 3,5-dimethoxyphenyl
• the use amount of the aryl Grignard compound is for example in a range of 1 mol to 10 mol and preferably in a range of 1 mol to 5 mol to 1 mol of the 3-(halo-substituted aryl)-2-thiazole-thione compound (6).
• Examples of a zinc compound to be used together with the aryl Grignard compound in the step A may be a zinc halide such as zinc chloride and zinc bromide.
• the use amount of the zinc compound is preferably in a range of 0.5 mol to 3 mol and more preferably in a range of 0.8 mol to 2 mol to 1 mol of the aryl Grignard compound.
• a solvent to be used in the case an arylboronic acid is used as the aryl compound (5) is preferably an organic solvent or a mixed solvent of an organic solvent and water.
• the organic solvent may be an ether solvent such as diethyl ether, methyl tert-butyl ether, and tetrahydrofuran; a halo hydrocarbon solvent such as chloroform and chlorobenzene; an aromatic solvent such as toluene and xylene; an alcohol solvent such as methanol, ethanol, isopropanol, and tert-butanol; and a nitrile solvent such as acetonitrile and propionitrile.
• a solvent to be used in the case an aryl Grignard compound is used as the aryl compound (5) is preferably an organic solvent.
• the organic solvent may be an ether solvent such as diethyl ether, methyl tert-butyl ether, and tetrahydrofuran; a halo hydrocarbon solvent such as chloroform and chlorobenzene; and an aromatic solvent such as toluene and xylene.
• the use amount of the solvent is not particularly limited and in consideration of the volume efficiency, it may be practically at highest 100 times as much as a (3-halo-substituted aryl)-2-thiazole-thione compound (6) on the basis of weight.
• the reaction in the step A may be carried out in normal pressure or in a pressurized condition.
• the reaction temperature is preferably in a range of ⁇ 20° C. to 150° C. and more preferably in a range of 0° C. to 100° C. If the reaction temperature is higher than 150° C., a byproduct having a high boiling point tends to be increased by a side reaction and if the reaction temperature is lower than ⁇ 20° C., the reactivity tends to be lowered.
• the reaction in the step A is preferably carried out by mixing a 3-(halo-substituted aryl)-2-thiazole-thione compound (6), the arylboronic acid, a palladium catalyst, a base compound, and if necessary, a solvent, and mixing and stirring the mixture at a prescribed temperature.
• the mixing order is not particularly limited.
• the reaction is preferably carried out by mixing the aryl Grignard compound, a palladium catalyst, a zinc compound, and if necessary, a solvent, thereafter adding a 3-(halo-substituted aryl)-2-thiazole-thione compound (6), and mixing and stirring the mixture at a prescribed temperature.
• the progression degree of the reaction may be confirmed by an analysis means such as gas chromatography, high performance liquid chromatography, thin-layer chromatography, nuclear magnetic resonance spectroscopic analysis, infrared absorption spectrometry, etc.
• the obtained reaction mixture generally contains a 3-(aryl-substituted aryl)-2-thiazole-thione compound (7) and on completion of the reaction, the 3-(aryl-substituted aryl)-2-thiazole-thione compound (7) is separated and taken out by concentration treatment or precipitation treatment after the palladium catalyst is removed by filtration or using a short column if necessary.
• the obtained 3-(aryl-substituted aryl)-2-thiazole-thione compound (7) may be refined further by a refining means such as recrystallization, column chromatography, etc.
• the 3-(aryl-substituted aryl)-2-thiazole-thione compound (7) is preferably the above-mentioned 3-(aryl-substituted aryl)-2-thiazole-thione compound (7′) and the above-mentioned 3-(aryl-substituted aryl)-2-thiazole-thione compound (7′′).
• R 1 and R 2 are independently a C 1-10 (more preferably a C 1-4 ) alkyl, or that R 1 and R 2 are bonded to each other to form a C 5-7 cycloalkene ring (more preferably a cyclohexene ring) together with the carbon atoms bonded to R 1 and R 2 ; it is more preferable that the carbon atom of the cycloalkene ring in the thiazolium ring S side (the 7th position in the cyclohexene ring) has a C 1-4 alkyl as a substituent; it is preferable that R 3 , R 4 , and R 5 are independently a hydrogen atom, a halogen atom, or a C 1-10 alkyl; and it is preferable that W 1 and W 2 are independently a C 6-10 aryl which may have a substituent.
• the aryl is more preferably phenyl having a substituent, even more preferably phenyl having a bulky group at one of the 3rd and the 5th positions, and still more preferably phenyl having a bulky group at the 3rd and the 5th positions.
• the bulky group may be phenyl, trifluoromethyl, tert-butyl, a chlorine atom, a bromine atom, an iodine atom, nitro, cyano, methoxycarbonyl, acyl, sulfo, and 3,4,5-trifluorophenyl.
• R 1 and R 2 are independently a C 1-10 (more preferably a C 1-4 ) alkyl, or that R 1 and R 2 are bonded to each other to form a C 5-7 cycloalkene ring (more preferably a cyclohexene ring) together with the carbon atoms bonded to R 1 and R 2 ; it is more preferable that the carbon atom of the cycloalkene ring in the thiazolium ring S side (the 7th position in the cyclohexene ring) has a C 1-4 alkyl as a substituent; it is preferable that R 3 , R 4 , and R 5 are independently a hydrogen atom or a C 1-10 alkyl; it is preferable that R 8 is a C 1-10 alkyl; and it is preferable that W 2 is a C 6-10 aryl which may have a substituent.
• the aryl is more preferably phenyl having a substituent, even more preferably phenyl having a bulky group at one of the 3rd and the 5th positions, and still more preferably phenyl having a bulky group at the 3rd and the 5th positions.
• the bulky group may be phenyl, trifluoromethyl, tert-butyl, a chlorine atom, a bromine atom, an iodine atom, nitro, cyano, methoxycarbonyl, acyl, sulfo, and 3,4,5-trifluorophenyl.
• Examples of a 3-(aryl-substituted aryl)-2-thiazole-thione compound (7) may be 4,5-dimethyl-3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-2(3H)-thiazole-thione, 4,5-dimethyl-3-[2,6-bis(3,5-di-tert-butylphenyl)-4-chlorophenyl]-2(3H)-thiazole-thione, 4,5-dimethyl-3-[2,6-bis(3,5-di-tert-butylphenyl)-4-methylphenyl]-2(3H)-thiazole-thione, 4,5-dimethyl-3-[2,6-bis(3,5-dichlorophenyl)phenyl]-2(3H)-thiazole-thione, 4,5-dimethyl-3-[2,6-bis(3,5-dibromophenyl)phenyl]-2(
• step B of oxidizing the 3-(aryl-substituted aryl)-2-thiazole-thione compound (7) obtained in the step A will be described.
• the oxidation in the step B is generally carried out by mixing the 3-(aryl-substituted aryl)-2-thiazole-thione compound (7) and an oxidizing agent.
• the oxidizing agent may be hydrogen peroxide, hypochlorous acid, and perbenzoic acid and preferably hydrogen peroxide.
• An aqueous solution of 10 wt. % to 60 wt. % of hydrogen peroxide is preferably used.
• the use amount of the oxidizing agent is preferably in a range of 2 mol to 20 mol and more preferably in a range of 2 mol to 10 mol to 1 mol of the 3-(aryl-substituted aryl)-2-thiazole-thione compound (7).
• the reaction in the step B is generally carried out in the presence of a solvent.
• a solvent to be used is an organic solvent or a mixed solvent of an organic solvent and water.
• the organic solvent may be a halo hydrocarbon solvent such as chloroform and chlorobenzene; an aromatic solvent such as toluene and xylene; a carboxylic acid solvent such as acetic acid and trifluoroacetic acid; and a nitrile solvent such as acetonitrile and propionitrile.
• the carboxylic acid solvent is preferable.
• the use amount of the organic solvent is not particularly limited and in consideration of the volume efficiency, it may be practically at highest 100 times as much as a (3-aryl-substituted aryl)-2-thiazole-thione compound (7) on the basis of weight.
• the reaction in the step B may be carried out in normal pressure or in a pressurized condition.
• the reaction temperature is preferably in a range of 0° C. to 150° C. and more preferably in a range of 20° C. to 100° C. If the reaction temperature is higher than 150° C., a byproduct having a high boiling point tends to be increased by a side reaction and if the reaction temperature is lower than 0° C., the reactivity tends to be lowered.
• the reaction in the step B is carried out by mixing and stirring the 3-(aryl-substituted aryl)-2-thiazole-thione compound (7), an oxidizing agent, and if necessary, a solvent at a desired temperature.
• the mixing order is not particularly limited.
• the progression degree of the reaction may be confirmed by an analysis means such as gas chromatography, high performance liquid chromatography, thin-layer chromatography, nuclear magnetic resonance spectroscopic analysis, infrared absorption spectrometry, etc.
• the produced thiazolium salt (8) is separated and taken out by forming a desired anion defined by X ⁇ by salt exchange operation and carrying out crystallization treatment.
• the salt exchange operation can be carried out by, for example, exchanging X ⁇ to chloride ion by carrying out extraction in an organic solvent such as a halo hydrocarbon solvent, an ether solvent, or the like in which the thiazolium salt (8) can be dissolved, mixing and stirring the resulting solvent with an aqueous saturated solution of sodium chloride, magnesium chloride, or the like, and separating liquid phases; thereafter removing the solvent, or dissolving the thiazolium salt (8) in an alcohol solvent; and then precipitating the thiazolium salt (8) in the form of a perchloric acid salt or a tetrafluoroboric acid salt by using lithium perchlorate or lithium tetrafluoroborate.
• an organic solvent such as a halo hydrocarbon solvent, an ether solvent, or the like in which the thiazolium salt (8) can be dissolved
• mixing and stirring the resulting solvent with an aqueous saturated solution of sodium chloride, magnesium chloride, or the like, and separating
• a thiazolium salt (1) in which W 0 ′ is a halogen atom can also be obtained by carrying out oxidation in the step B using a 3-(halo-substituted aryl)-2-thiazole-thione compound (6) in place of a 3-(aryl-substituted aryl)-2-thiazole-thione compound (7).
• the present invention is characterized by carrying out a coupling reaction (that is, the present reaction) of an aldehyde compound in the presence of a thiazolium salt (1) and a base compound.
• the present reaction is advantageous in terms of improvement of selectivity in production of an ⁇ -hydroxy ketone compound per unit catalyst amount.
• the present invention is characterized by carrying out a coupling reaction (that is, the present reaction) of an aldehyde compound in the presence of a thiazol-2-ylidene defined by a formula (1-2) (hereinafter, sometimes referred to as a thiazol-2-ylidene (1-2)).
• thiazolium salt (1) a thiazolium salt (1) and a base compound produces a thiazol-2-ylidene (1-2) which can work as a catalyst for the coupling reaction of an aldehyde compound.
• a thiazol-2-ylidene (1-2) may have stability changed in accordance with its structure and those which are stabilized by a bulky substituent in a carbene position can be observed by NMR and IR.
• the present reaction can be performed by mixing the thiazolium salt (1), a base compound, and an aldehyde compound with no need of confirming production of the thiazol-2-ylidene (1-2) and also can be performed by producing the thiazol-2-ylidene (1-2) from only the thiazolium salt (1) and a base compound and then adding an aldehyde compound.
• the structure of the thiazol-2-ylidene (1-2) is formed by pulling out hydrogen in the form of proton from the carbon atom at the 2nd position of the thiazolium ring of the thiazolium salt (1) by the basic group and neutralizing the carbon atom together with X ⁇ anion to produce carbene in the carbon atom at the 2nd position.
• the thiazol-2-ylidene (1-2) is preferably a thiazol-2-ylidene defined by a formula (1′-2) (hereinafter, referred to also as a thiazol-2-ylidene (1′-2)) and a thiazol-2-ylidene defined by a formula (1′′-2) (hereinafter, referred to also as a thiazol-2-ylidene (1′′-2)).
• Examples of a thiazol-2-ylidene (1′-2) are 3-[2,6-di(phenyl)phenyl]-thiazol-2-ylidene, 3-[2,6-di(phenyl)phenyl]-4,5-dimethylthiazol-2-ylidene, 3-[2,6-di(phenyl)phenyl]-4,5-diethylthiazol-2-ylidene, 3-[2,6-di(phenyl)phenyl]-4-methyl-5-acylthiazol-2-ylidene, 3-[2,6-di(phenyl)phenyl]-4-methyl-5-methoxycarbonylthiazol-2-ylidene, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-thiazol-2-ylidene, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-thiazol-2-ylid
• Examples of a thiazol-2-ylidene (1′′-2) are 3-[2-(phenyl)-6-methylphenyl]-thiazol-2-ylidene, 3-[2-(phenyl)-6-methylphenyl]-4,5-dimethylthiazol-2-ylidene, 3-[2-(phenyl)-6-ethylphenyl]-4,5-diethylthiazol-2-ylidene, 3-[2-(phenyl)-6-methylphenyl]-4-methyl-5-acylthiazol-2-ylidene, 3-[2-(phenyl)-6-ethylphenyl]-4-methyl-5-methoxycarbonylthiazol-2-ylidene, 3-[2-(3,5-di-tert-butylphenyl)-6-methylphenyl]-thiazol-2-ylidene, 3-[2-(3,5-di-tert-butylphenyl)-6-methylphenyl]-thiazol-2-y
• Such thiazol-2-ylidenes (1′-2) and (1′′-2) are novel compounds and as described in the present invention, a thiazolium salt (1) and a base compound can be reacted.
• the method described in JP 5-221913 A can be employed for synthesizing these compounds. That is, thiazol-2-ylidenes (1′-2) and (1′′-2) can be produced by a method of heating a precursor obtained by adding an alcohol or carbon dioxide to the carbon atom at the 2nd position of a thiazol-2-ylidene.
• Thiazol-2-ylidenes (1′-2) and (1′′-2) are preferably 3-[2,6-di(phenyl)phenyl]-4,5-dimethylthiazol-2-ylidene, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5-dimethylthiazol-2-ylidene, 3-[(2,6-diphenyl-3,5-diisopropyl)phenyl]-4,5-dimethylthiazol-2-ylidene, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydrobenzothiazol-2-ylidene, 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydro-7-ethylbenzothiazol-2-ylidene, 3-[2,6-bis(3,5-
• the coupling reaction in the present invention may include a homo-coupling reaction for coupling a single aldehyde compound and a cross-coupling reaction for coupling different aldehyde compounds.
• the homo-coupling reaction may be a homo-coupling reaction of an aldehyde compound defined by a formula (2)
• R 6 denotes a hydrogen atom, an alkyl which may have a substituent, an aryl which may have a substituent, or a heteroaryl which may have a substituent
• the cross-coupling reaction may be a cross-coupling reaction of an aldehyde (2) and an aldehyde compound defined by a formula (4)
• R 7 is different from R 6 and denotes a hydrogen atom, an alkyl which may have a substituent, an aryl which may have a substituent, or a heteroaryl which may have a substituent
• aldehyde (4) an aldehyde
• R 6 and R 7 denotes the same as described above, or their mixture.
• the production ratio differs in accordance with the types of R 5 and R 6 and one of them may be produced selectively in some cases.
• Examples of an alkyl denoted by R 6 and R 7 may be C 1-10 straight chain, branched chain, and cyclic alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, decyl, cyclopropyl, 2,2-dimethylcyclopropyl, cyclopentyl, cyclohexyl, and menthyl.
• cyclic alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, decyl, cyclopropyl, 2,2-dimethylcyclopropyl, cyclopentyl, cyclohexyl, and menthyl.
• Examples of a substituent which the alkyl may have may be a C 1-6 alkoxy, which may have a fluorine atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and trifluoromethyloxy; a C 6-10 -aryl-containing C 1-10 alkoxy, which may have a C 1-10 alkoxy, such as benzyloxy, 4-methylbenzyloxy, and 4-methoxybenzyloxy; a C 1-10 alkoxy having a C 6-10 aryloxy-containing C 6-10 aryl such as 3-phenoxybenzyloxy; a C 6-10 aryloxy, which may have a C 1-10 alkoxy, such as phenoxy, 2-methylphenoxy, 4-methylphenoxy, and 4-methoxyphenoxy; a C 6-10 aryloxy-containing C 6-10 aryloxy such as 3-phenoxyphenoxy; a C 2-10 acyl,
• Examples of an alkyl having a substituent may be chloromethyl, fluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, methoxyethyl, methoxycarbonylmethyl, 1-ethoxycarbonyl-2,2-dimethyl-3-cyclopropyl, and 2-methylthioethyl.
• Examples of an aryl denoted by R 6 and R 7 may be a C 6-20 aryl such as phenyl, 2-methylphenyl, 4-methylphenyl, and naphthyl.
• Examples of a substituent which the aryl may have may be a C 1-10 alkyl containing a fluorine atom such as fluoromethyl and trifluoromethyl; a C 1-10 alkyl containing a C 1-10 alkoxy such as methoxymethyl, ethoxymethyl, and methoxyethyl; a C 1-10 alkoxy which may have a fluorine atom or a C 1-10 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, cyclopentyloxy, fluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, and methoxyethoxy; a C 6-10 aryloxy which may have a C 1-10 alkoxy such as phenoxy, 2-methylphenoxy, 4-methylphenoxy, and 4-methoxyphenoxy; a C 6-10 aryloxy
• Examples of a heteroaryl in R 6 and R 7 may be a C 4-10 heteroaryl containing at least one hetero atom such as a nitrogen atom, an oxygen atom, and a sulfur atom, such as pyridyl, furyl, and 5-methylfuryl.
• Examples of a substituent which the heteroaryl may have may be a C 1-10 alkyl containing a fluorine atom such as fluoromethyl and trifluoromethyl; a C 1-10 alkyl containing a C 1-10 alkoxy such as methoxymethyl, ethoxymethyl, and methoxyethyl; a C 1-10 alkoxy which may have a fluorine atom or a C 1-10 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, cyclopentyloxy, fluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, and methoxyethoxy; a C 6-10 aryloxy which may have a C 1-10 alkoxy such as phenoxy, 2-methylphenoxy, 4-methylphenoxy, and 4-methoxyphenoxy; a C 6-10 n ary
• heteroaryl having a substituent examples include 2-chloropyridyl.
• Examples of an aldehyde (2) and an aldehyde (4) may be an aliphatic aldehyde such as formaldehyde, acetaldehyde, propionaldehyde, n-butyl aldehyde, cyclopentane carboaldehyde, cyclohexane carboaldehyde, 2-methylpropanal, 2,2-dimethylpropanal, 3-methylthiopropanal, 2,2-dimethylbutanal, 1-methylcyclohexane carboaldehyde, 2,2-dimethylnonanal, and methyl 2,2-dimethyl-3-oxopropanate; an aromatic aldehyde such as benzaldehyde, 4-fluorobenzaldehyde, 4-nitrobenzaldehyde, 3-bromobenzaldehyde, 2-chlorobenzaldehyde, 4-methylbenzaldehyde, 3-methoxybenzaldehyde, 3,4,5-trimeth
• an aldehyde (2) and an aldehyde (4) polymers of formaldehyde such as paraformaldehyde may also be usable and an aldehyde may be used in a state of co-existing with water, e.g., formalin water.
• an aldehyde (2) and the aldehyde (4) are different from each other. It is preferable to use formaldehyde co-existing with water as the aldehyde (4) and it is more preferable to use 3-methylthiopropanal as the aldehyde (2).
• the present reaction is preferable to be caused in the presence of a solvent.
• the solvent may be an aromatic hydrocarbon solvent such as toluene, xylene, and chlorobenzene; an aliphatic hydrocarbon solvent such as pentane, hexane, and heptane; a halo hydrocarbon solvent such as dichloromethane, dichloroethane, and chloroform; an ether solvent such as diethyl ether, methyl tert-butyl ether, and tetrahydrofuran; an ester solvent such as ethyl acetate; an amide solvent such as N,N-dimethylformamide and N,N-dimethylacetamide; and an alcohol solvent such as methanol and ethanol.
• aromatic hydrocarbon solvent such as toluene, xylene, and chlorobenzene
• an aliphatic hydrocarbon solvent such as pentane, hexane, and heptane
• a halo hydrocarbon solvent such as dichloromethane, dichloroethane,
• aqueous solution such as formalin water; that is, formaldehyde co-existing with water; is used as an aldehyde compound
• the reaction can be caused efficiently by using a solvent which has no compatibility with water.
• a solvent which has no compatibility with water may be preferably the above-mentioned aromatic hydrocarbon solvents; aliphatic hydrocarbon solvents; and halo hydrocarbon solvents.
• the use amount of the solvent may be, in consideration of the volume efficiency, practically preferably 100 parts by weight or less to 1 part by weight of an aldehyde compound.
• the use amount of a thiazolium salt (1) is preferably 0.00001 to 0.2 mol and more preferably 0.0001 to 0.05 mol to 1 mol of an aldehyde compound.
• the use amount of a thiazolium salt (1) is preferably 0.00001 to 0.2 mol and more preferably 0.0001 to 0.05 mol to 1 mol of one of aldehyde compounds.
• the present reaction is a cross-coupling reaction, generally, 1 mol or more of one aldehyde compound is used to 1 mol of the other aldehyde compound.
• a base compound to be used in the present reaction may be at least one kind of compound selected from the group consisting of organic bases, alkali metal salts such as alkali metal carbonates, alkaline earth metal salts such as alkaline earth metal carbonates.
• Examples of an organic base may be a tertiary amine such as triethylamine, trioctylamine, diisopropylethylamine, and 4-dimethylaminopyridine; a nitrogen-containing cyclic compound such as 1,8-diazabicyclo[5.4.0]-7-undecene, 1,5,7-triazabicyclo[4,4,0]-5-decene; a nitrogen-containing aromatic compound such as pyridine and imidazole; and an alkali metal alkoxide such as sodium methoxide and sodium ethoxide.
• a tertiary amine such as triethylamine, trioctylamine, diisopropylethylamine, and 4-dimethylaminopyridine
• a nitrogen-containing cyclic compound such as 1,8-diazabicyclo[5.4.0]-7-undecene, 1,5,7-triazabicyclo[4,4,0]-5-decene
• Examples of an alkali metal carbonate may be sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, lithium carbonate, and lithium hydrogen carbonate.
• Examples of an alkaline earth metal carbonate may be magnesium carbonate and calcium carbonate.
• a base compound is preferably an organic base.
• the use amount of the base compound is preferably in a range of 0.1 to 2 mol and more preferably in a range of 0.5 to 1.5 mol to 1 mol of the thiazolium salt (1).
• the present reaction may be carried out in the presence of carbon dioxide or in a gas atmosphere inactive to the reaction without using carbon dioxide.
• Carbon dioxide to be used in the present reaction may be gaseous or solid-phase (dry ice) or in supercritical state.
• Gaseous carbon dioxide may be diluted with an inert gas such as nitrogen.
• the use amount of carbon dioxide is preferably 1 mol or more to 1 mol in total of base compounds and its upper limit is not particularly limited and in consideration of the productivity, it may be 1000 mol or lower.
• Examples of the gas inactive to the reaction may be nitrogen, argon, and helium and its use amount is not particularly limited.
• the reaction temperature of the present reaction may be in a range of ⁇ 20° C. to 200° C.
• the present reaction is caused by, for example, a method of mixing an aldehyde compound, a thiazolium salt (1), a base compound, and if necessary, a solvent.
• the mixing order is not particularly limited and a method to be employed preferably may be a method of mixing an aldehyde compound, a thiazolium salt (1) and if necessary a solvent and thereafter adding a base compound or a method of mixing a thiazolium salt (1), a base compound, and if necessary a solvent, and thereafter adding an aldehyde compound to the mixture.
• a method in which the present reaction is carried out in carbon dioxide or in an inactive gas atmosphere is employed more preferably.
• the present reaction may be carried out in normal pressure or in a pressurized condition, for example, by pressurizing with gaseous carbon dioxide or a gas inactive to the reaction.
• the progression degree of the reaction may be confirmed by an analysis means such as gas chromatography, high performance liquid chromatography, thin-layer chromatography, NMR, IR, etc.
• An ⁇ -hydroxy ketone compound can be taken out, for example, by concentrating the obtained reaction mixture on completion of the present reaction.
• the taken out ⁇ -hydroxy ketone compound may be refined further by a refining means such as distillation, column chromatography, etc.
• Examples of an ⁇ -hydroxy ketone compound to be obtained in the above-mentioned manner may be 2-hydroxyacetaldehyde, 3-hydroxy-2-butanone, 4-hydroxy-3-hexanone, 1,6-dimethylthio-4-hydroxy-3-hexanone, 5-hydroxy-4-octanone, 2-hydroxy-1-phenyl-ethanone, 2-hydroxy-1-(4-chlorophenyl)-ethanone, 2-hydroxy-1-phenyl-2-phenylethanone, 2-hydroxy-1-(4-methoxyphenyl)-2-phenylethanone, 2-hydroxy-1-(4-chlorophenyl)-2-phenylethanone, 2-hydroxy-1-(2-fluorophenyl)-2-phenylethanone, 4-(methylthio)-2-oxo-1-butanol, 1-hydroxy-2-propanone, 1-hydroxy-2-butanone, 1-hydroxy-2-pentanone, and 2-hydroxy-1-cyclohexanone.
• a 100 mL flask purged with nitrogen was loaded with 0.9 g of formic acid and 0.82 g of acetic anhydride and the mixture was stirred at room temperature for 1 hour and then cooled to 5° C.
• a solution obtained by dissolving 3.03 g of 2,6-bis(3,5-di-tert-butylphenyl)aniline in 15 g of chloroform was dropwise added to the resulting reaction solution at 5° C. for 30 minutes. Thereafter, the obtained reaction solution was kept warm and stirred at room temperature for 3 hours.
• the obtained reaction mixture was mixed with 20 g of chloroform, neutralized and washed with 15 g of a saturated sodium hydrogen carbonate solution and washed with 15 g of water and then the formed chloroform layer was dried and concentrated by anhydrous sodium sulfate to obtain 3.2 g of a white solid material.
• the obtained crystal was confirmed to be 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5-dimethylthiazolium chloride by 1 H-NMR.
• reaction solution was heated to room temperature and kept at the temperature and stirred for 12 hours. After mixed with 80 g of water, the obtained reaction mixture was subjected to extraction with 80 g of diethyl ether and the formed organic layer was washed with water, dried by anhydrous magnesium sulfate, mixed with 15 g of a molecular sieve (MS-3A), and dried overnight.
• MS-3A molecular sieve
• a 100 mL flask purged with nitrogen was loaded with 0.31 g of formic acid and 0.29 g of acetic anhydride and the mixture was stirred at room temperature for 1 hour and then cooled to 5° C.
• a solution obtained by dissolving 0.74 g of (2,6-diphenyl-3,5-diisopropyl)aniline in 5 g of chloroform was dropwise added to the resulting reaction solution at 5° C. for 30 minutes. Thereafter, the obtained reaction solution was kept warm and stirred at room temperature for 3 hours. The precipitated crystal was filtered from the obtained reaction mixture, washed with water, and dried to obtain 0.4 g of a white crystal.
• a 100 mL flask purged with nitrogen was loaded with 10 g of 2,6-dibromoaniline and 30 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 1.6 g of a sodium hydroxide powder in 1.5 g of water and the mixture was stirred for 10 minutes. Further, 3.0 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 4.3 g of 3-chloro-2-butanone, heated to room temperature, and stirred for 1 hour.
• a 100 mL flask purged with nitrogen was loaded with 5 g of 2,6-dichloroaniline and 10 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 1.3 g of a sodium hydroxide powder in 1.2 g of water and the mixture was stirred for 10 minutes. Further, 2.4 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 4.1 g of 2-chlorocyclohexanone, heated to room temperature, and stirred for 1 hour.
• a 100 mL flask purged with nitrogen was loaded with 2 g of 2,6-dibromoaniline and 6 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 320 mg of a sodium hydroxide powder in 300 mg of water and the mixture was stirred for 10 minutes. Further, 610 mg of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 1.06 g of 2-chlorocyclohexanone, heated to room temperature, and stirred for 1 hour.
• a 100 mL flask purged with nitrogen was loaded with 10 g of 2,4,6-tribromoaniline and 20 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 1.21 g of a sodium hydroxide powder in 1.1 g of water and the mixture was stirred for 10 minutes. Further, 2.3 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 4.0 g of 2-chlorocyclohexanone, heated to room temperature, and stirred for 1 hour.
• a 100 mL flask purged with nitrogen was loaded with 5 g of 2,6-dibromoaniline and 10 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 800 mg of a sodium hydroxide powder in 700 mg of water and the mixture was stirred for 10 minutes. Further, 1.51 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 2.7 g of 3-chloroacetylacetone, heated to room temperature, and stirred for 1 hour.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (after adsorption in 50 g of silica gel and elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 350 mg of a light yellow crystal.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (after adsorption in 50 g of silica gel and elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 350 mg of a light yellow crystal.
• a 100 mL flask purged with nitrogen was loaded with 500 mg of 4,5-dimethyl-3-(2,6-dibromophenyl)-2(3H)-thiazole-thione synthesized in Example 4, 240 mg of 3,5-dimethoxyphenylboronic acid, 10 g of tetrahydrofuran, 120 mg of (2-di-tert-butylphosphino)biphenyl, 1.2 g of cesium fluoride, and 30 mg of palladium acetate and the mixture was heated to 50° C. and stirred for 18 hours. During the stirring, at the moment after 9 hours, 240 mg of 3,5-dimethoxyphenylboronic acid was additionally added.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (adsorption in 50 g of silica gel and thereafter, elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 580 mg of a light yellow oil.
• This crystal was confirmed to be a mixture containing 60% (gas chromatography area normalization method) of 4,5-dimethyl-3-[2,6-bis(3,5-dimethoxyphenyl)phenyl]-2(3H)-thiazole-thione by GC-MS.
• the solvent was removed by distillation from the obtained chloroform layer to obtain 320 mg of a light brown powder.
• the powder was mixed with 10 g of toluene and dissolved matter was removed to obtain 230 mg of a white powder. This powder was confirmed to be 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydrobenzothiazolium chloride by 1 H-NMR.
• a 100 mL flask purged with nitrogen was loaded with 350 mg (purity 50%) of 4,5,6,7-tetrahydro-3-(2,6-phenylphenyl)-2(3H)-benzothiazole-thione synthesized in Example 10, 2 g of acetic acid, and 600 mg of 30 wt. % hydrogen peroxide water and the mixture was heated to 50° C. and stirred for 30 minutes. After the reaction, the solvent was removed by distillation and 10 g of methanol was added to the residue and then methanol was removed by distillation. The obtained residue was mixed with 10 g of chloroform and 10 g of saturated salt water and extracted and separated by a separatory funnel.
• a 100 mL flask purged with nitrogen was loaded with 850 mg (purity 30%) of 4,5-dimethyl-3-[2,6-bis(3,5-di-trifluoromethylphenyl)phenyl]-2(3H)-thiazole-thione synthesized in Example 11, 2 g of acetic acid, and 600 mg of 30 wt. % hydrogen peroxide water and the mixture was heated to 50° C. and stirred for 30 minutes. After the reaction, the solvent was removed by distillation and 10 g of methanol was added to the residue and then methanol was removed by distillation. The obtained residue was mixed with 10 g of chloroform and 10 g of saturated salt water and extracted and separated by a separatory funnel.
• a 100 mL flask purged with nitrogen was loaded with 580 mg (purity 60%) of 4,5-dimethyl-3-[2,6-bis(3,5-dimethoxyphenyl)phenyl]-2(3H)-thiazole-thione synthesized in Example 12, 2 g of acetic acid, and 600 mg of 30 wt. % hydrogen peroxide water and the mixture was heated to 50° C. and stirred for 30 minutes. After the reaction, the solvent was removed by distillation and 10 g of methanol was added to the residue and then methanol was removed by distillation. The obtained residue was mixed with 10 g of chloroform and 10 g of saturated salt water and extracted and separated by a separatory funnel.
• a 100 mL flask purged with nitrogen was loaded with 300 mg of 4,5-dimethyl-3-(2,6-dibromophenyl]-2(3H)-thiazole-thione synthesized in Example 4, 2 g of acetic acid, and 500 mg of 30 wt. % hydrogen peroxide water and the mixture was heated to 50° C. and stirred for 60 minutes. After the reaction, the solvent was removed by distillation and 10 g of methanol was added to the residue and then methanol was removed by distillation. The obtained residue was mixed with 10 g of chloroform and 10 g of saturated salt water and extracted and separated by a separatory funnel.
• a 100 mL flask purged with nitrogen was loaded with 300 mg of 4,5,6,7-tetrahydro-3-(2,6-dibromophenyl)-2(3H)-benzothiazole-thione synthesized in Example 6, 2 g of acetic acid, and 600 mg of 30 wt. % hydrogen peroxide water and the mixture was heated to 60° C. and stirred for 60 minutes. After the reaction, the solvent was removed by distillation and 10 g of methanol was added to the residue and then methanol was removed by distillation. The obtained residue was mixed with 10 g of chloroform and 10 g of saturated salt water and extracted and separated by a separatory funnel.
• the obtained reaction mixture was cooled to room temperature to obtain a reaction mixture containing 4-(methylthio)-2-oxo-1-butanol.
• the yield of 4-(methylthio)-2-oxo-1-butanol, a cross-coupling product was 4% and 60% of 3-methylthiopropanal, a raw material, was recovered.
• the yield of 1,6-dimethylthio-4-hydroxy-3-hexanone, a homo-coupling product was 1%.
• the production ratio after 6 hour-reaction time was as follows.
• a 50 mL Schlenk flask purged with nitrogen was loaded with 1.38 g of 3-methylthiopropanal, 400 mg of paraformaldehyde, 40 mg of 3-[2,6-di(phenyl)phenyl]-4,5-dimethylthiazolium chloride obtained in Example 1, and 2.8 g of tetrahydrofuran.
• the obtained mixture was heated to 40° C., mixed with 16 mg of 1,8-diazabicyclo[5.4.0]-7-undecene, and then stirred at 40° C. for 1.5 hours.
• the obtained reaction mixture was cooled to room temperature to obtain a reaction mixture containing 4-hydroxy-3-hexanone. According to analysis by a gas chromatography internal standard method, the yield of 4-hydroxy-3-hexanone was 22% and 75% of propanal was recovered.
• a 50 mL Schlenk flask purged with nitrogen was loaded with 841 mg of benzaldehyde, 480 mg of paraformaldehyde, 30 mg of 3-[2,6-di(phenyl)phenyl]-4,5-dimethylthiazolium chloride obtained in Example 1, and 3 g of toluene.
• the obtained mixture was heated to 60° C., mixed with 24 mg of 1,8-diazabicyclo[5.4.0]-7-undecene while being stirred, and then stirred at 60° C. for 6 hours.
• the obtained reaction mixture was cooled to room temperature to obtain a reaction mixture containing 2-hydroxy-1-phenyl-ethanone. According to analysis by a gas chromatography internal standard method, the yield of 2-hydroxy-1-phenyl-ethanone was 21% and 77% of benzaldehyde was recovered.
• the production ratio after 6 hour-reaction time was as follows.
• a 100 mL four-mouth flask purged with nitrogen was loaded with 10 g of 3-methylthiopropanal, 15 g of 35 wt. % formalin water, 30 mg of 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydrobenzothiazolium chloride obtained in Example 13, and 20 g of toluene.
• 1 g of dry ice was added to the flask, generated gaseous carbon dioxide was discharged to lower the pressure to normal pressure. After the obtained mixture was heated to 50° C.
• the production ratio after 8 hour-reaction time was as follows.
• a 50 mL Schlenk flask purged with nitrogen was loaded with 960 mg of 3-methylthiopropanal, 1.1 g of 35 wt. % formalin water, 30 mg of 3-[2,6-bis(3,5-di-trifluoromethylphenyl)phenyl]-4,5-dimethylthiazolium chloride obtained in Example 15, and 2 g of toluene.
• 500 mg of dry ice was added to the flask, generated gaseous carbon dioxide was discharged to lower the pressure to normal pressure. After the obtained mixture was heated to 50° C.
• a 50 mL Schlenk flask purged with nitrogen was loaded with 921 mg of benzaldehyde, 480 mg of paraformaldehyde, 23 mg of 3-(2,6-dibromophenyl)-4,5,6,7-tetrahydrobenzothiazolium chloride obtained in Example 18, and 2 g of toluene.
• the obtained mixture was heated to 50° C., mixed with 12 mg of 1,8-diazabicyclo[5.4.0]-7-undecene, and then stirred at 50° C. for 6 hours.
• the obtained reaction mixture was cooled to room temperature to obtain a reaction mixture containing 2-hydroxy-1-phenyl-ethanone.
• the yield of 2-hydroxy-1-phenyl-ethanone, a cross-coupling product was 26%
• the yield of 2-hydroxy-1-phenyl-2-phenylethanone, a homo-coupling product was 16%
• 58% of benzaldehyde, a raw material was recovered.
• a 100 mL flask purged with nitrogen was loaded with 5 g of 2-bromo-6-methylaniline and 10 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution containing 1.07 g of a sodium hydroxide powder dissolved in 1.0 g of water and the mixture was stirred for 10 minutes.
• 2.0 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 3.56 g of 2-chlorocyclohexanone, heated to room temperature, and stirred for 1 hour.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (adsorption in 50 g of silica gel and thereafter, elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 380 mg of a light yellow crystal.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (adsorption in 50 g of silica gel and thereafter, elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 360 mg of a light yellow crystal.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (adsorption in 50 g of silica gel and thereafter, elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 380 mg of a light yellow crystal.
• the obtained residue was mixed with 10 g of chloroform and 10 g of saturated salt water and extracted and separated by a separatory funnel.
• the solvent was removed by distillation from the obtained chloroform layer to obtain 300 mg of a light brown powder.
• This powder was confirmed to be 3-[2,6-bis(3,5-dichlorophenyl)phenyl]-4,5,6,7-tetrahydrobenzothiazolium chloride by 1 H-NMR. Yield 79%
• the obtained residue was mixed with 10 g of chloroform and 10 g of saturated salt water and extracted and separated by a separatory funnel.
• the solvent was removed by distillation from the obtained chloroform layer to obtain 310 mg of a light brown powder.
• This powder was confirmed to be 3-[2,6-bis(3,5-dibromophenyl)phenyl]-4,5,6,7-tetrahydrobenzothiazolium chloride by 1 H-NMR. Yield 73%
• a 200 mL flask purged with nitrogen was loaded with 5 g of 2,6-dibromo-4-methylaniline and 10 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with 755 mg of a sodium hydroxide powder dissolved in 800 mg of water and the mixture was stirred for 10 minutes.
• 1.4 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 2.5 g of 2-chlorocyclohexanone, heated to room temperature, and stirred for 1 hour.
• reaction solution When the resulting reaction solution was mixed with 50 g of water and stirred for 30 minutes, the reaction solution was separated into a gum-like solid and a water layer and therefore, the water layer was removed by decantation and the gum-like solid was washed with 50 g of water.
• This solid was mixed with 20 g of ethanol and 2 g of concentrated hydrochloric acid and heated and stirred at 60° C. for 30 minutes. After the reaction, the reaction mixture was cooled to room temperature, and the precipitated crystal was filtered and successively washed with 10 g of ethanol and dried to obtain 2.5 g of a light yellow powder.
• a 200 mL flask purged with nitrogen was loaded with 10 g of 2,6-dibromo-4-chloroaniline and 20 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with 1.4 g of a sodium hydroxide powder dissolved in 1.2 g of water and the mixture was stirred for 10 minutes. Further, 2.7 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 4.6 g of 2-chlorocyclohexanone, heated to room temperature, and stirred for 1 hour.
• reaction solution When the resulting reaction solution was mixed with 50 g of water and stirred for 30 minutes, the reaction solution was separated into a gum-like solid and a water layer and therefore, the water layer was removed by decantation and the gum-like solid was washed with 50 g of water.
• This solid was mixed with 50 g of ethanol and 5 g of concentrated hydrochloric acid and heated and stirred at 60° C. for 30 minutes. After the reaction, the reaction mixture was cooled to room temperature, and the precipitated crystal was filtered and successively washed with 10 g of ethanol and dried to obtain 8.9 g of a light yellow powder.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (adsorption in 50 g of silica gel and thereafter, elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 420 mg of a light yellow crystal.
• a 50 mL flask purged with nitrogen was loaded with 5 mg of palladium acetate, 20 mg of (2-di-tert-butylphosphino)biphenyl, and 5 g of tetrahydrofuran and the mixture was observed at 20° C. for 10 minutes. Further, the flask was loaded with 140 mg of zinc chloride and 1 mL of a tetrahydrofuran solution of phenylmagnesium bromide (2 mol/L concentration, produced by Tokyo Kasei Kogyo Co., Ltd.) and the mixture was stirred at room temperature for 10 minutes.
• This mixed solution was mixed with 200 mg of 4,5-dimethyl-3-(2,6-dibromophenyl)-2(3H)-thiazole-thione synthesized in Example 4 and heated to 40° C. and stirred for 8 hours. After the reaction, the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel. The formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• a 100 mL flask purged with nitrogen was loaded with 190 mg of 4,5-dimethyl-3-(2,6-diphenylphenyl]-2(3H)-thiazole-thione synthesized in Example 53, 2 g of acetic acid, and 800 mg of 30 wt. % hydrogen peroxide water and the mixture was heated to 60° C. and stirred for 30 minutes.
• a 200 mL flask purged with nitrogen was loaded with 5 g of 2,6-dibromoaniline and 10 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 800 mg of a sodium hydroxide powder in 700 mg of water and the mixture was stirred for 10 minutes. Further, 1.51 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 2.92 g of 2-chlorocycloheptanone, heated to room temperature, and stirred for 1 hour.
• a 100 mL flask purged with nitrogen was loaded with 300 mg of 3,4,5,6,7-hexahydro-3-(2,6-dibromophenyl)-2H-cycloheptathiazole-2-thione synthesized in Example 55, 510 mg of 3,5-di-tert-butylphenylboronic acid, 10 g of tetrahydrofuran, 70 mg of (2-di-tert-butylphosphino)biphenyl, 700 mg of cesium fluoride, and 17 mg of palladium acetate and the mixture was heated to 50° C. and stirred for 8 hours.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (adsorption in 50 g of silica gel and thereafter, elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 440 mg of a light yellow crystal.
• a 200 mL flask purged with nitrogen was loaded with 5 g of 2,6-dibromoaniline and 10 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 800 mg of a sodium hydroxide powder in 700 mg of water and the mixture was stirred for 10 minutes. Further, 1.52 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 2.4 g of 2-chlorocyclopentanone, heated to room temperature, and stirred for 1 hour.
• a 100 mL flask purged with nitrogen was loaded with 250 mg of 3,4,5,6-tetrahydro-3-(2,6-dibromophenyl)-2H-cyclopentathiazole-2-thione synthesized in Example 58, 432 mg of 3,5-di-tert-butylphenylboronic acid, 10 g of tetrahydrofuran, 60 mg of (2-di-tert-butylphosphino)biphenyl, 600 mg of cesium fluoride, and 14 mg of palladium acetate and the mixture was heated to 60° C. and stirred for 8 hours.
• a 200 mL flask purged with nitrogen was loaded with 8 g of 2,6-dibromoaniline and 15 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 1.28 g of a sodium hydroxide powder in 1100 mg of water and the mixture was stirred for 10 minutes. Further, 2.42 g of carbon disulfide was added for 10 minutes and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 5.6 g of 2-bromo-3,3-dimethylbutylaldehyde, heated to room temperature, and stirred for 1 hour.
• the resulting reaction solution was mixed with 50 g of water and stirred for 30 minutes, a crystal was precipitated, and the crystal was separated by filtration and dried to obtain 10.6 g of a light yellow crystal.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (adsorption in 60 g of silica gel and thereafter, elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 460 mg of a light yellow oil.
• a 100 mL flask purged with nitrogen was loaded with 1.2 g of 2,6-dibromoaniline and 6 g of dimethyl sulfoxide and the mixture was cooled to 5° C. while being stirred.
• the flask was further loaded with a solution obtained by dissolving 200 mg of a sodium hydroxide powder in 200 mg of water and the mixture was stirred for 10 minutes. Further, 370 mg of carbon disulfide was added and the mixture was heated to room temperature and stirred for 1 hour and cooled to 5° C.
• the resulting reaction solution was mixed with 1.0 g of 2-bromo-3-ethylcyclohexanone, heated to room temperature, and stirred for 1 hour.
• reaction solution When the resulting reaction solution was mixed with 10 g of water and stirred for 30 minutes, the reaction solution was separated into a gum-like solid and a water layer and therefore, the water layer was removed by decantation and the gum-like solid was washed with 10 g of water.
• This solid was mixed with 10 g of ethanol and 1 g of concentrated hydrochloric acid and heated and stirred at 60° C. for 30 minutes. After the reaction, the reaction mixture was cooled to room temperature, and ethanol was removed by distillation. The obtained residue was mixed with 20 g of n-heptane and the precipitated crystal was separated by filtration and dried to obtain 400 mg of a light yellow powder.
• the reaction solution was mixed with 10 g of ethyl acetate and 20 g of water and washed and separated by a separatory funnel.
• the formed organic layer was again washed and separated with 10 g of water and thereafter dried with magnesium sulfate and the solvent was removed by distillation.
• the obtained residue was refined by a silica gel short column (adsorption in 50 g of silica gel and thereafter, elution with 300 mL of chloroform) and the solvent was removed by distillation to obtain 500 mg of a light yellow crystal.
• the obtained residue was mixed with 10 g of chloroform and 10 g of saturated salt water and extracted and separated by a separatory funnel.
• the solvent was removed by distillation from the obtained chloroform layer and the obtained residue was mixed with 10 g of methyl-tert-butyl ether and the precipitated crystal was separated by filtration and dried to obtain 160 mg of a white powder.
• This powder was confirmed to be 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydro-7-ethylbenzothiazolium chloride by 1 H-NMR.
• the production ratio after 8 hour-reaction time was as follows.
• the obtained reaction mixture was cooled to room temperature to obtain a reaction mixture containing 4-(methylthio)-2-oxo-1-butanol.
• the yield of 4-(methylthio)-2-oxo-1-butanol, a cross-coupling product, was 33% and 65% of 3-methylthiopropanal, a raw material, was recovered.
• a 200 mL four-mouth flask equipped with semilunar-shape stirring blades made of Teflon was loaded with 12.2 g of 3-methylthiopropanal, 14.7 g of 38 wt. % formalin water, 16 mg of 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydro-7-ethyl-benzothiazolium chloride obtained in Example 66, and 25 g of toluene. After the obtained mixture was heated to 70° C.
• the water layer was extracted three times with 5 g of toluene and the obtained toluene layer was mixed with the initially separated toluene layer to obtain a reaction mixture containing 4-(methylthio)-2-oxo-1-butanol.
• the yield of 4-(methylthio)-2-oxo-1-butanol, a cross-coupling product was 67% and 32% of 3-methylthiopropanal, a raw material, remained.
• Toluene was removed by distillation from the toluene solution to obtain 14 g of a light yellow oil. Since the oil was solidified when ice-cooled, the oil was mixed with 10 g of toluene and subjected to recrystallization, filtration, and drying to obtain 4.0 g of 4-(methylthio)-2-oxo-butanol in the form of a white platy crystal with a GC purity (area percentage) of 94%. In the same manner, 1.0 g of 4-(methylthio)-2-oxo-1-butanol with a GC purity (area percentage) of 94% was obtained from the filtrate.
• an NMR tube was loaded with 11 mg of 3-[2,6-bis(3,5-di-tert-butylphenyl)phenyl]-4,5,6,7-tetrahydrobenzothiazolium chloride obtained in Example 13.
• the NMR tube was further loaded with a mixed solution obtained by dispersing 10 mg of sodium-tert-butoxide in 0.7 mL of deuterated toluene and tightly closed.
• the invention provides an innovative method for producing an ⁇ -hydroxy ketone compound.
• the invention is advantageous in terms of improvement of selectivity in production of an ⁇ -hydroxy ketone compound per unit catalyst amount.

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• 2012
  • 2012-08-27 WO PCT/JP2012/072277 patent/WO2013035650A1/en active Application Filing
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